Many animals, man included, live in areas providing insufficient iodine (I) for optimal health. Degrees of I deficiency (ID) vary from mild-moderate to very severe, with quali- and quantitatively different negative consequences. To understand the mechanisms involved in adaptation to different grades of ID, we fed rats a low-iodine diet, plus additions resulting in a 250-fold range of I daily available to the thyroid, ranging from 5 mug (adequate) down to 0.02 microg I. We measured thyroid weight, total I, T(4), T(3), and type I 5' iodothyronine deiodinase (D1) activity, TSH, T(4), free T(4), and T(3) in plasma, T(4) and T(3) in 11 tissues, and two 5' deiodinase isoenzymes in four. TSH-independent thyroid autoregulation plays an important role in addition to TSH-dependent mechanisms in the adaptation to ID, avoiding a decrease of T(3) in plasma and most tissues, despite a marked decrease of plasma T(4), whereas extrathyroidal responses of D2 mitigate T(3) deficiency in tissues in which T(3) is mostly generated from T(4). We focused on mild and moderate ID, the least investigated experimentally, despite its current frequency in industrialized countries. The novel and important finding of our study is that thyroid status cannot be defined for the animal as a whole: at all grades of ID, T(3) is simultaneously elevated, normal, and low in different tissues. Present findings in mild-moderate ID draw attention to the importance, for man, of the resulting hypothyroxinemia that may affect mental functions and neurodevelopment of the inhabitants, even when they do not have the increased TSH or clinical hypothyroidism, often wrongly attributed to them.